bims-medebr 2023-03-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–03–12
thirty-six papers selected by
Regina F. Fernández, Johns Hopkins University

S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR2,4, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health.
Brain ethanol metabolism and mitochondria.
Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation.
Sex-Specific Response of the Brain Free Oxylipin Profile to Soluble Epoxide Hydrolase Inhibition.
Systematic review of brain and blood lipidomics in Alzheimer's disease mouse models.
NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis.
Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration.
Association between Arachidonic Acid and the Risk of Schizophrenia: A Cross-National Study and Mendelian Randomization Analysis.
Normal appearing white matter metabolite pattern and sex differences in multiple sclerosis patients compared to healthy controls.
Enrichment of Brain n-3 Docosapentaenoic Acid (DPA) and Retinal n-3 Eicosapentaenoic Acid (EPA) in Lambs Fed Nannochloropsis oceanica Microalga.
Impressive efficacy of the ketogenic diet in a KCNQ2 encephalopathy infant: a case report and exhaustive literature review.
Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve.
Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults.
Classic ketogenic diet in parenteral nutrition in a GLUT1DS patient: Doing more with less in an acute surgical setting.
Characterization of Dendritic Cell Metabolism by Flow Cytometry.
Intermittent fasting ameliorates neuronal ferroptosis and cognitive impairment in mice after traumatic brain injury.
Sphingolipids and impaired hypoxic stress responses in Huntington disease.
Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study.
Intracranial Pressure Variability: A New Potential Metric of Cerebral Ischemia and Energy Metabolic Dysfunction in Aneurysmal Subarachnoid Hemorrhage?
Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency.
Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin.
Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.
Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome.
Defining metabolic migraine with a distinct subgroup of patients with suboptimal inflammatory and metabolic markers.
Impact of dietary n-3 polyunsaturated fatty acid intake during the perinatal and post-weaning periods on the phospholipid and ganglioside composition of olfactory tissues.
Omega-3 polyunsaturated fatty acids alleviate early brain injury after traumatic brain injury by inhibiting neuroinflammation and necroptosis.
Importance of fatty acid binding proteins in cellular function and organismal metabolism.
Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.
Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases.
Tissue-Specific Sex Difference in Mouse Eye and Brain Metabolome Under Fed and Fasted States.
Haste makes waste: staged suppression of autophagic-lysosomal pathway in microglia promotes the efficient clearance of myelin debris.
Competitive, multi-objective and compartmented Flux Balance Analysis for addressing tissue specific Inborn Errors of Metabolism.
Sphingolipids in neurodegenerative diseases.
Lipids at the Nexus between Cerebrovascular Disease and Vascular Dementia: The Impact of HDL-Cholesterol and Ceramides.
Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.
The effect of statins on the differentiation and function of central nervous system cells.

Int J Mol Sci. 2023 Feb 26. pii: 4581. [Epub ahead of print]24(5):

S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR2,4, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health.

Shah Alam, Sumaiya Yasmeen Afsar, Gerhild Van Echten-Deckert.

  Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically lethal, affecting, inter alia, the anterior neural tube closure. However, an excess of S1P due to mutations in S1P-lyase (SGPL1), the enzyme responsible for its constitutive removal, is also harmful. Of note, the gene SGPL1 maps to a region prone to mutations in several human cancers and also in S1P-lyase insufficiency syndrome (SPLIS) characterized by several symptoms, including peripheral and central neurological defects. Here, we investigated the impact of S1P on astrocytes in a mouse model with the neural-targeted ablation of SGPL1. We found that SGPL1 deficiency, and hence the accumulation of its substrate, S1P, causes the elevated expression of glycolytic enzymes and preferentially directs pyruvate into the tricarboxylic acid (TCA) cycle through its receptors (S1PR2,4). In addition, the activity of TCA regulatory enzymes was increased, and consequently, so was the cellular ATP content. The high energy load activates the mammalian target of rapamycin (mTOR), thus keeping astrocytic autophagy in check. Possible consequences for the viability of neurons are discussed.

Keywords:  S1P-lyase (SGPL1); SPLIS; autophagy; glucose metabolism; sphingosine 1-phosphate (S1P)

DOI:  https://doi.org/10.3390/ijms24054581
Curr Top Biochem Res. 2022 ;23 1-13

Brain ethanol metabolism and mitochondria.

Jaylyn Waddell, Mary C McKenna, Tibor Kristian.

Alcohol abuse and dependence in humans causes an extreme shift in metabolism for which the human brain is not evolutionarily prepared. Oxidation of ethanol and acetaldehyde are not regulated, making ethanol a dominating metabolic substrate that prevents the activity of enzymes from oxidizing their usual endogenous substrates. The enzymes required to oxidize ethanol across the variety of affected tissues all produce acetaldehyde which is then converted to acetate by aldehyde dehydrogenases (ALDHs). ALDHs are NAD+-dependent enzymes, and mitochondrial ALDH2 is likely the primary contributor to ethanol-derived acetaldehyde clearance in cells. Metabolism of alcohol has several adverse effects on mitochondria including increased free radical levels, hyperacetylation of mitochondrial proteins, and excessive mitochondrial fragmentation. This review discusses the role of astrocytic and neuronal mitochondria in ethanol metabolism that contributes to the acute and chronic changes in mitochondrial function and morphology, that might promote tolerance, dependence and withdrawal. We also propose potential modes of therapeutic intervention to reduce the toxicity of chronic alcohol consumption.

Keywords: brain; ethanol; mitochondria
Cells. 2023 Feb 21. pii: 683. [Epub ahead of print]12(5):

Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation.

Ellen A Silva, Ana P Dalla Costa, Juliana S Ruas, Edilene S Siqueira-Santos, Annelise Francisco, Roger F Castilho.

  Understanding the role of astrocytes in the development of the nervous system and neurodegenerative disorders implies a necessary knowledge of the oxidative metabolism of proliferating astrocytes. The electron flux through mitochondrial respiratory complexes and oxidative phosphorylation may impact the growth and viability of these astrocytes. Here, we aimed at assessing to which extent mitochondrial oxidative metabolism is required for astrocyte survival and proliferation. Primary astrocytes from the neonatal mouse cortex were cultured in a physiologically relevant medium with the addition of piericidin A or oligomycin at concentrations that fully inhibit complex I-linked respiration and ATP synthase, respectively. The presence of these mitochondrial inhibitors for up to 6 days in a culture medium elicited only minor effects on astrocyte growth. Moreover, neither the morphology nor the proportion of glial fibrillary acidic protein-positive astrocytes in culture was affected by piericidin A or oligomycin. Metabolic characterization of the astrocytes showed a relevant glycolytic metabolism under basal conditions, despite functional oxidative phosphorylation and large spare respiratory capacity. Our data suggest that astrocytes in primary culture can sustainably proliferate when their energy metabolism relies only on aerobic glycolysis since their growth and survival do not require electron flux through respiratory complex I or oxidative phosphorylation.

Keywords:  OXPHOS; astrocytes; bioenergetic; mitochondria; oligomycin; piericidin A

DOI:  https://doi.org/10.3390/cells12050683
Nutrients. 2023 Feb 28. pii: 1214. [Epub ahead of print]15(5):

Sex-Specific Response of the Brain Free Oxylipin Profile to Soluble Epoxide Hydrolase Inhibition.

Jennifer E Norman, Saivageethi Nuthikattu, Dragan Milenkovic, John C Rutledge, Amparo C Villablanca.

  Oxylipins are the oxidation products of polyunsaturated fatty acids and have been implicated in neurodegenerative disorders, including dementia. Soluble epoxide hydrolase (sEH) converts epoxy-fatty acids to their corresponding diols, is found in the brain, and its inhibition is a treatment target for dementia. In this study, male and female C57Bl/6J mice were treated with an sEH inhibitor (sEHI), trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks to comprehensively study the effect of sEH inhibition on the brain oxylipin profile, and modulation by sex. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to measure the profile of 53 free oxylipins in the brain. More oxylipins were modified by the inhibitor in males than in females (19 versus 3, respectively) and favored a more neuroprotective profile. Most were downstream of lipoxygenase and cytochrome p450 in males, and cyclooxygenase and lipoxygenase in females. The inhibitor-associated oxylipin changes were unrelated to serum insulin, glucose, cholesterol, or female estrous cycle. The inhibitor affected behavior and cognitive function as measured by open field and Y-maze tests in males, but not females. These findings are novel and important to our understanding of sexual dimorphism in the brain's response to sEHI and may help inform sex-specific treatment targets.

Keywords:  brain; cognitive function; dementia; oxylipin; sex differences; soluble epoxide hydrolase

DOI:  https://doi.org/10.3390/nu15051214
Prog Lipid Res. 2023 Mar 05. pii: S0163-7827(23)00013-9. [Epub ahead of print]90 101223

Systematic review of brain and blood lipidomics in Alzheimer's disease mouse models.

Laura Ferré-González, Ana Lloret, Consuelo Cháfer-Pericás.

  Alzheimer's disease (AD) diagnosis is based on invasive and expensive biomarkers. Regarding AD pathophysiological mechanisms, there is evidence of a link between AD and aberrant lipid homeostasis. Alterations in lipid composition have been observed in blood and brain samples, and transgenic mouse models represent a promising approach. Nevertheless, there is great variability among studies in mice for the determination of different types of lipids in targeted and untargeted methods. It could be explained by the different variables (model, age, sex, analytical technique), and experimental conditions used. The aim of this work is to review the studies on lipid alteration in brain tissue and blood samples from AD mouse models, focusing on different experimental parameters. As result, great disparity has been observed among the reviewed studies. Brain studies showed an increase in gangliosides, sphingomyelins, lysophospholipids and monounsaturated fatty acids and a decrease in sulfatides. In contrast, blood studies showed an increase in phosphoglycerides, sterols, diacylglycerols, triacylglycerols and polyunsaturated fatty acids, and a decrease in phospholipids, lysophospholipids and monounsaturated fatty acids. Thus, lipids are closely related to AD, and a consensus on lipidomics studies could be used as a diagnostic tool and providing insight into the mechanisms involved in AD.

Keywords:  Alzheimer's disease; Brain; Lipidomics; Lipids; Mouse model; Plasma

DOI:  https://doi.org/10.1016/j.plipres.2023.101223
Cell Chem Biol. 2023 Feb 24. pii: S2451-9456(23)00056-9. [Epub ahead of print]

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis.

Prakash Kharel, Naveen Kumar Singhal, Thulasi Mahendran, Nicole West, Brintha Croos, Joram Rana, Lindsey Smith, Ernest Freeman, Ansuman Chattopadhyay, Jennifer McDonough, Soumitra Basu.

  RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Extensive RNA oxidation occurs within the neurons in multiple sclerosis (MS) brains. Here, we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) is one such transcript, whose translation product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in a reduction in its cognate protein, thus lowering the NAA level. This hypothesis is supported by our studies on cells, an animal model, and postmortem human MS brain. Reduced brain NAA level hampers myelin integrity making neuronal axons more susceptible to damage, which contributes to MS neurodegeneration. Overall, this work provides a framework for a mechanistic understanding of the link between RNA oxidation and neurodegeneration.

Keywords:  N-acetyl aspartate; RNA oxidation; demyelination; multiple sclerosis; neurodegeneration; oxo-guanosine

DOI:  https://doi.org/10.1016/j.chembiol.2023.02.007
Sci Adv. 2023 Mar 10. 9(10): eadd1101

Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration.

Rodney M Ritzel, Yun Li, Yun Jiao, Zhuofan Lei, Sarah J Doran, Junyun He, Rami A Shahror, Rebecca J Henry, Romeesa Khan, Chunfeng Tan, Shaolin Liu, Bogdan A Stoica, Alan I Faden, Gregory Szeto, David J Loane, Junfang Wu.

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months old) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.

DOI: https://doi.org/10.1126/sciadv.add1101
Nutrients. 2023 Feb 27. pii: 1195. [Epub ahead of print]15(5):

Association between Arachidonic Acid and the Risk of Schizophrenia: A Cross-National Study and Mendelian Randomization Analysis.

Yan Gao, Xiaowen Hu, Dandan Wang, Jie Jiang, Minghui Li, Ying Qing, Xuhan Yang, Juan Zhang, Yue Zhang, Chunling Wan.

  Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (rAA = -0.577, p < 0.01; rω-6 LCPUFA = -0.626, p < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia (ORAA = 0.986, ORGLA = 0.148). In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.

Keywords:  Mendelian randomization; arachidonic acid; cross-national study; long-chain polyunsaturated fatty acid; schizophrenia

DOI:  https://doi.org/10.3390/nu15051195
Folia Med (Plovdiv). 2022 Oct 31. 64(5): 746-753

Normal appearing white matter metabolite pattern and sex differences in multiple sclerosis patients compared to healthy controls.

Vasilena Petrova, Krasimir Genov.

   INTRODUCTION: Proton magnetic resonance spectroscopy (PrMRS) detects changes in brain metabolite levels in vivo.

Keywords:  disconnection gender magnetic resonance spectroscopy

DOI:  https://doi.org/10.3897/folmed.64.e66002
Animals (Basel). 2023 Feb 24. pii: 828. [Epub ahead of print]13(5):

Enrichment of Brain n-3 Docosapentaenoic Acid (DPA) and Retinal n-3 Eicosapentaenoic Acid (EPA) in Lambs Fed Nannochloropsis oceanica Microalga.

Ana C M Vítor, Jorge J Correia, Susana P Alves, Rui J B Bessa.

  Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have special physiological functions in both brain and retinal tissues that are related to the modulation of inflammatory processes and direct effects on neuronal membrane fluidity, impacting mental and visual health. Among them, the long-chain (LC) n-3 PUFAs, as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are of special importance. Scarce data are available about the fatty acid (FA) composition of the ruminant brain in response to dietary intervention. However, we decided to examine the brain and retina FA composition of lambs supplemented with an EPA-rich microalga feed for 21 days, as it is known that despite the extensive biohydrogenation of dietary PUFAs in the rumen, ruminants can selectively accumulate some n-3 LC-PUFAs in their brain and retinal tissues. Twenty-eight male lambs were fed a control diet, or the same diet further supplemented with Nannochloropsis sp. microalga. Their brains and retina were collected for FA characterization. Overall, the brain FA profile remained unchanged, with little alteration in omega-3 docosapentaenoic acid (DPA) enhancement in both the hippocampus and prefrontal cortex. Retinal tissues were particularly responsive to the dietary intervention, with a 4.5-fold enhancement of EPA in the freeze-dried-fed lambs compared with the control lambs. We conclude that retinal tissues are sensitive to short-term n-3 PUFA supplementation in lambs.

Keywords:  dimethyl acetal; fatty acid; hippocampus; prefrontal cortex

DOI:  https://doi.org/10.3390/ani13050828
Transl Pediatr. 2023 Feb 28. 12(2): 292-300

Impressive efficacy of the ketogenic diet in a KCNQ2 encephalopathy infant: a case report and exhaustive literature review.

Raffaele Falsaperla, Simona Domenica Marino, Giulia Salomone, Francesca Madia, Silvia Marino, Lucia Giovanna Tardino, Bruna Scalia, Martino Ruggieri.

   Background: KCNQ2 encephalopathy is characterized by neonatal-onset epilepsy and developmental impairment, due to "de novo" KCNQ2 pathogenic variants. According to literature data, sodium channel blocking agents appear to be the best treatment options for the disease. Reports describing the use of ketogenic diet (KD) in the KCNQ2 pediatric population are limited. The non-conservative amino acid substitution p.Ser122Leu in KCNQ2 is associated with a broad spectrum of inheritance modalities, clinical phenotypes and outcomes; no previous reports of the same variant treated with KD are available in literature.
Case Description: We described a 22-month-old female with seizure onset on day 2 of life. At three months of age, she presented refractory status epilepticus (SE) that did not respond to midazolam and carbamazepine, which was added once a "de novo" p.Ser122Leu KCNQ2 variant was demonstrated. KD was the only treatment that led to cessation of seizures. The baby maintained seizures remission and achieved neurodevelopmental milestones.
Conclusions: To define an overt genotype-phenotype correlation for KCNQ2 pathogenic variants is a challenge; we propose the KD as a valuable treatment for refractory seizures and impaired neurodevelopment in infants harboring "de novo" mutations in the KCNQ2 gene.

Keywords:  Developmental and epileptic encephalopathy; KCNQ2 gene; case report; infant; ketogenic diet (KD)

DOI:  https://doi.org/10.21037/tp-22-258
eNeuro. 2023 Mar 09. pii: ENEURO.0353-22.2023. [Epub ahead of print]

Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve.

Tomofumi Takenaka, Yuichiro Ohnishi, Masamichi Yamamoto, Daiki Setoyama, Haruhiko Kishima.

  Wallerian Degeneration (WD) occurs in the early stages of numerous neurological disorders, and clarifying WD pathology is crucial for the advancement of neurological therapies. Adenosine triphosphate (ATP) is acknowledged as one of the key pathological substances in WD. The ATP-related pathological pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. While, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. However, little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.Significance StatementWallerian degeneration after axotomy is associated with decreasing ATP levels. To maintain ATP levels, Schwann cells activate the glycolytic systems and produce monocarboxylate, which is transported to axons via MCTs. Axons also activate the glycolysis system to obtain ATP, and inactivate TCA cycle due to mitochondrial degeneration. The glycolysis with MCT-induced monocarboxylate transport contributes to the ATP production in degenerative axons.

Keywords:  ATP; Wallerian degeneration; glycolytic system; in vivo imaging; mitochondria

DOI:  https://doi.org/10.1523/ENEURO.0353-22.2023
Nutrients. 2023 Feb 24. pii: 1148. [Epub ahead of print]15(5):

Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults.

Christina Heidt, Manfred Fobker, Mary Newport, Reinhold Feldmann, Tobias Fischer, Thorsten Marquardt.

  MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the perceived potential benefits. However, consumption of carbohydrates with MCTs and untoward gastrointestinal side effects, especially at higher doses, could decrease the sustainability of the ketogenic response. This single-center study investigated the impact of consuming carbohydrate as glucose with MCT oil compared to MCT alone on the BHB response. The effects of MCT oil versus MCT oil plus glucose on blood glucose, insulin response, levels of C8, C10, BHB, and cognitive function were determined, and side effects were monitored. A significant plasma BHB increase with a peak at 60 min was observed in 19 healthy participants (24.4 ± 3.9 years) after consuming MCT oil alone, and a more delayed but slightly higher peak was observed after consuming MCT oil plus glucose. A significant increase in blood glucose and insulin levels occurred only after MCT oil plus glucose intake. The overall mean plasma levels of C8 and C10 were higher with the intake of MCT oil alone. MCT oil plus glucose consumption showed improved scores for the arithmetic and vocabulary subtests.

Keywords:  beta-hydroxybutyrate; cognitive function; decanoic acid; glucose; insulin; ketogenic diet; medium-chain fatty acids; octanoic acid

DOI:  https://doi.org/10.3390/nu15051148
Front Nutr. 2023 ;10 1114386

Classic ketogenic diet in parenteral nutrition in a GLUT1DS patient: Doing more with less in an acute surgical setting.

Valentina De Giorgis, Cinzia Ferraris, Mario Leo Brena, Giorgio Farris, Valerio Gentilino, Monica Guglielmetti, Claudia Marazzi, Ludovica Pasca, Claudia Trentani, Anna Tagliabue, Costanza Varesio.

  Ketogenic Dietary Treatments (KDTs) are to date the gold-standard treatment for glucose transporter type 1 (GLUT1) deficiency syndrome. Administration of KDTs is generally per os; however, in some conditions including the acute gastro-enteric post-surgical setting, short-term parenteral (PN) administration might be needed. We report the case of a 14-year-old GLUT1DS patient, following classic KDT for many years, who underwent urgent laparoscopic appendectomy. PN-KDT was required, after 1 day of fasting. No ad hoc PN-KDTs products were available and the patient received infusions of OLIMEL N4 (Baxter). On the sixth day postoperatively enteral nutrition was progressively reintroduced. The outcome was optimal with rapid recovery and no exacerbation of neurological manifestations. Our patient is the first pediatric patient with GLUT1DS in chronic treatment with KDT efficiently treated with exclusive PN for five days. This case reports on real-word management and the ideal recommendations for PN-KDT in an acute surgical setting.

Keywords:  GLUT1 deficiency syndrome; appendicitis; classic ketogenic diet; ketone bodies; parenteral nutrition; surgery

DOI:  https://doi.org/10.3389/fnut.2023.1114386
Methods Mol Biol. 2023 ;2618 219-237

Characterization of Dendritic Cell Metabolism by Flow Cytometry.

Eline C Brombacher, Thiago A Patente, Marjolein Quik, Bart Everts.

  In response to different stimuli, dendritic cells (DCs) undergo metabolic reprogramming to support their function. Here we describe how fluorescent dyes and antibody-based approaches can be used to assess various metabolic parameters of DCs including glycolysis, lipid metabolism, mitochondrial activity, and the activity of important sensors and regulators of cellular metabolism, mTOR and AMPK. These assays can be performed using standard flow cytometry and will allow for the determination of metabolic properties of DC populations at single-cell level and to characterize metabolic heterogeneity within them.

Keywords:  Dendritic cells; Flow cytometry; Glucose; Lipids; Metabolism; Mitochondria; ROS

DOI:  https://doi.org/10.1007/978-1-0716-2938-3_16
Nutrition. 2023 Feb 04. pii: S0899-9007(23)00022-9. [Epub ahead of print]109 111992

Intermittent fasting ameliorates neuronal ferroptosis and cognitive impairment in mice after traumatic brain injury.

Qiuyun Yang, Manrui Li, Jinyuan Liu, Lingxuan Zhang, Ruixuan Yuan, Yang Xu, Jingwen Zheng, Shuqiang Cao, Hao Dai, Miao Liao, Meili Lv, Xiaogang Chen, Yadong Guo, Xiaoqi Xie, Lin Zhang, Xiameng Chen, Weibo Liang.

  Ferroptosis, a newly characterized form of programmed cell death that results from lipid peroxidation and mitochondrial dysfunction, has been demonstrated to be involved in the pathogenesis of traumatic brain injury (TBI). Scientific evidence has shown that intermittent fasting (IF) reduces both the lipid peroxidation and the mitochondrial dysfunction, raising the question of whether IF affects the ferroptosis induced by TBI. Here, based on an established TBI animal model, we examine the effects of IF on the activation of ferroptosis pathway as well as related outcomes. We uncovered that a 1-mo IF elevated the protective Gpx4 and Hspb1 expression, and partly abolished the increase of Nfe2l2, Slc7a11, Alox8, Steap3, and Nox2 in the cortex, which were induced by TBI. Furthermore, the characteristic cellular damage induced by ferroptosis was alleviated by IF, as revealed by Perls' Prussian blue staining, Nissl staining, and transmission electron microscope examination. Consistently, we examined the outcomes of mice subjected to TBI and found an improved cognitive function of the IF mice. In sum, our study demonstrated, to our knowledge for the first time, that a 1-mo IF regimen partly ameliorates ferroptosis in the cortex of mice subjected to TBI, which potentially contributes to a lessening of cognitive impairment.

Keywords:  Cognition; Cortex; Ferroptosis; Intermittent fasting; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.nut.2023.111992
Prog Lipid Res. 2023 Mar 08. pii: S0163-7827(23)00014-0. [Epub ahead of print] 101224

Sphingolipids and impaired hypoxic stress responses in Huntington disease.

Johannes Burtscher, Giuseppe Pepe, Niran Maharjan, Nathan Riguet, Alba Di Pardo, Vittorio Maglione, Grégoire P Millet.

  Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated. Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease. Based on the crucial role of sphingolipids in maintaining cellular homeostasis, the dynamic regulation of sphingolipids upon insults and their involvement in cellular stress responses, we hypothesize that maladaptations or blunted adaptations, especially following cellular stress due to reduced oxygen supply (hypoxia) contribute to the development of pathology in HD. We review how sphingolipids shape cellular energy metabolism and control proteostasis and suggest how these functions may fail in HD and in combination with additional insults. Finally, we evaluate the potential of improving cellular resilience in HD by conditioning approaches (improving the efficiency of cellular stress responses) and the role of sphingolipids therein. Sphingolipid metabolism is crucial for cellular homeostasis and for adaptations following cellular stress, including hypoxia. Inadequate cellular management of hypoxic stress likely contributes to HD progression, and sphingolipids are potential mediators. Targeting sphingolipids and the hypoxic stress response are novel treatment strategies for HD.

Keywords:  Huntington disease; Sphingolipids; conditioning; hypoxia; mitochondria

DOI:  https://doi.org/10.1016/j.plipres.2023.101224
Mov Disord. 2023 Mar 11.

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11 C]UCB-J and [18 F]FDG PET Study.

Katrine B Andersen, Allan K Hansen, Anna Christina Schacht, Jacob Horsager, Hanne Gottrup, Henriette Klit, Erik H Danielsen, Kathleen L Poston, Nicola Pavese, David J Brooks, Per Borghammer.

   BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor.
OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease.
METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level.
RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density.
CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Parkinson's disease; [11C]UCB-J; [18F]FDG PET; dementia; synapse

DOI:  https://doi.org/10.1002/mds.29375
J Neurosurg Anesthesiol. 2023 Apr 01. 35(2): 208-214

Intracranial Pressure Variability: A New Potential Metric of Cerebral Ischemia and Energy Metabolic Dysfunction in Aneurysmal Subarachnoid Hemorrhage?

Teodor Svedung Wettervik, Timothy Howells, Anders Hånell, Elisabeth Ronne-Engström, Anders Lewén, Per Enblad.

BACKGROUND: It was recently reported that lower intracranial pressure variability (ICPV) is associated with delayed ischemic neurological deficits and unfavorable outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to determine whether lower ICPV also correlated with worse cerebral energy metabolism after aSAH.
METHODS: A total of 75 aSAH patients treated in the neurointensive care unit at Uppsala University Hospital, Sweden between 2008 and 2018 and with both intracranial pressure and cerebral microdialysis (MD) monitoring during the first 10 days after ictus were included in this retrospective study. ICPV was calculated with a bandpass filter limited to intracranial pressure slow waves with a wavelength of 55 to 15 seconds. Cerebral energy metabolites were measured hourly with MD. The monitoring period was divided into 3 phases; early (days 1 to 3), early vasospasm (days 4 to 6.5), and late vasospasm (days 6.5 to 10).
RESULTS: Lower ICPV was associated with lower MD-glucose in the late vasospasm phase, lower MD-pyruvate in the early vasospasm phases, and higher MD-lactate-pyruvate ratio (LPR) in the early and late vasospasm phases. Lower ICPV was associated with poor cerebral substrate supply (LPR >25 and pyruvate <120 µM) rather than mitochondrial failure (LPR >25 and pyruvate >120 µM). There was no association between ICPV and delayed ischemic neurological deficit, but lower ICPV in both vasospasm phases correlated with unfavorable outcomes.
CONCLUSION: Lower ICPV was associated with an increased risk for disturbed cerebral energy metabolism and worse clinical outcomes in aSAH patients, possibly explained by a vasospasm-related decrease in cerebral blood volume dynamics and cerebral ischemia.

DOI: https://doi.org/10.1097/ANA.0000000000000816
Acta Neuropathol Commun. 2023 Mar 07. 11(1): 34

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency.

Elsa Ghirardini, Giulia Sagona, Angel Marquez-Galera, Francesco Calugi, Carmen M Navarron, Francesco Cacciante, Siwei Chen, Federica Di Vetta, Lorenzo Dadà, Raffaele Mazziotti, Leonardo Lupori, Elena Putignano, Pierre Baldi, Jose P Lopez-Atalaya, Tommaso Pizzorusso, Laura Baroncelli.

  Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

Keywords:  Creatine transporter deficiency; Energy metabolism; Neurodevelopmental disorders; Parvalbumin neurons; Synapse

DOI:  https://doi.org/10.1186/s40478-023-01533-w
iScience. 2023 Mar 17. 26(3): 106150

Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin.

Susan J Qualls-Histed, Casey P Nielsen, Jason A MacGurn.

  Glucose transporters are gatekeepers of cellular glucose metabolism. Understanding how their activity is regulated can provide insight into mechanisms of glucose homeostasis and diseases arising from dysregulation of glucose transport. Glucose stimulates endocytosis of the human glucose transporter GLUT1, but several important questions remain surrounding the intracellular trafficking itinerary of GLUT1. Here, we report that increased glucose availability triggers lysosomal trafficking of GLUT1 in HeLa cells, with a subpopulation of GLUT1 routed through ESCRT-associated late endosomes. This itinerary requires the arrestin-like protein TXNIP, which interacts with both clathrin and E3 ubiquitin ligases to promote GLUT1 lysosomal trafficking. We also find that glucose stimulates GLUT1 ubiquitylation, which promotes its lysosomal trafficking. Our results suggest that excess glucose first triggers TXNIP-mediated endocytosis of GLUT1 and, subsequently, ubiquitylation to promote lysosomal trafficking. Our findings underscore how complex coordination of multiple regulators is required for fine-tuning of GLUT1 stability at the cell surface.

Keywords:  Biological sciences; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.106150
Brain Commun. 2023 ;5(2): fcad032

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.

W Brad Hubbard, Hemendra J Vekaria, Olivia J Kalimon, Malinda L Spry, Emily P Brown, Todd J Kilbaugh, Patrick G Sullivan.

  Pioglitazone interacts through the mitochondrial protein mitoNEET to improve brain bioenergetics following traumatic brain injury. To provide broader evidence regarding the therapeutic effects of pioglitazone after traumatic brain injury, the current study is focused on immediate and delayed therapy in a model of mild brain contusion. To assess pioglitazone therapy on mitochondrial bioenergetics in cortex and hippocampus, we use a technique to isolate subpopulations of total, glia-enriched and synaptic mitochondria. Pioglitazone treatment was initially administered at either 0.25, 3, 12 or 24 h following mild controlled cortical impact. At 48 h post-injury, ipsilateral cortex and hippocampus were dissected and mitochondrial fractions were isolated. Maximal mitochondrial respiration injury-induced deficits were observed in total and synaptic fractions, and 0.25 h pioglitazone treatment following mild controlled cortical impact was able to restore respiration to sham levels. While there are no injury-induced deficits in hippocampal fractions, we do find that 3 h pioglitazone treatment after mild controlled cortical impact can significantly increase maximal mitochondrial bioenergetics compared to vehicle-treated mild controlled cortical impact group. However, delayed pioglitazone treatment initiated at either 3 or 24 h after mild brain contusion does not improve spared cortical tissue. We demonstrate that synaptic mitochondrial deficits following mild focal brain contusion can be restored with early initiation of pioglitazone treatment. Further investigation is needed to determine functional improvements with pioglitazone beyond that of overt cortical tissue sparing following mild contusion traumatic brain injury.

Keywords:  TBI; bioenergetics; mitoNEET; oxidative stress; traumatic brain injury

DOI:  https://doi.org/10.1093/braincomms/fcad032
Front Cell Neurosci. 2023 ;17 1114914

Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome.

Cuihong Zhou, Xinxin Zhao, Xinxu Ma, Hongzhe Ma, Rui Li, Guangtao Hu, Huaning Wang, Zhengwu Peng, Min Cai.

  Introduction: Compelling evidence indicates that a single sub-anesthetic dose of (S)-ketamine elicits rapid and robust antidepressant effects. However, the underlying mechanisms behind the antidepressant effects of (S)-ketamine remain unclear. Methods: Here, using a chronic variable stress (CVS) model in mice, we analyzed changes inthe lipid compositions of the hippocampus and prefrontal cortex (PFC) with a mass spectrometry-based lipidomic approach. Results: Similar to previous research outcomes, the current study also showed that (S)-ketamine reversed depressive-like behaviors in mice produced by CVS procedures. Moreover, CVS induced changes inthe lipid compositions of the hippocampus and PFC, notably in the contents of sphingolipids, glycerolipids, and fatty acyls. With the administration of (S)-ketamine, CVS-induced lipid disturbances were partially normalized, particularly in the hippocampus. Conclusion: Altogether, our results indicated that (S)-ketamine could rescue CVS-induced depressive-like behaviors in mice through region-specific modulation of the brain lipidome, contributing to the understanding of (S)-ketamine's antidepressant effects.

Keywords:  (S)-ketamine; CVS: chronic variable stress; hippocampus; lipidomic; major depressive disorder; prefrontal cortex

DOI:  https://doi.org/10.3389/fncel.2023.1114914
Sci Rep. 2023 Mar 07. 13(1): 3787

Defining metabolic migraine with a distinct subgroup of patients with suboptimal inflammatory and metabolic markers.

Elena C Gross, Niveditha Putananickal, Anna-Lena Orsini, Jean Schoenen, Dirk Fischer, Adrian Soto-Mota.

Emerging evidence suggest migraine is a response to cerebral energy deficiency or oxidative stress in the brain. Beta-hydroxybutyrate (BHB) is likely able to circumvent some of the meta-bolic abnormalities reported in migraine. Exogenous BHB was given to test this assumption and, in this post-hoc analysis, multiple metabolic biomarkers were identified to predict clinical improvements. A randomized clinical trial, involving 41 patients with episodic migraine. Each treatment period was 12 weeks long, followed by eight weeks of washout phase / second run-in phase before entering the corresponding second treatment period. The primary endpoint was the number of migraine days in the last 4 weeks of treatment adjusted for baseline. BHB re-sponders were identified (those with at least a 3-day reduction in migraine days over placebo) and its predictors were evaluated using Akaike's Information Criterion (AIC) stepwise boot-strapped analysis and logistic regression. Responder analysis showed that metabolic markers could identify a "metabolic migraine" subgroup, which responded to BHB with a 5.7 migraine days reduction compared to the placebo. This analysis provides further support for a "metabolic migraine" subtype. Additionally, these analyses identified low-cost and easily accessible biomarkers that could guide recruitment in future research on this subgroup of patients.This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233.

DOI: https://doi.org/10.1038/s41598-023-28499-y
Prostaglandins Leukot Essent Fatty Acids. 2023 Feb 26. pii: S0952-3278(23)00025-X. [Epub ahead of print]191 102556

Impact of dietary n-3 polyunsaturated fatty acid intake during the perinatal and post-weaning periods on the phospholipid and ganglioside composition of olfactory tissues.

Spiro Khoury, Vanessa Soubeyre, Stéphanie Cabaret, Stéphane Grégoire, Esther Mézière, Elodie Masson, Xavier Grosmaitre, Lionel Bretillon, Olivier Berdeaux, Niyazi Acar, Anne Marie Le Bon.

  The olfactory mucosa (OM) and olfactory bulb (OB) are neuronal tissues that contribute to the early processing of olfactory information. They contain significant amounts of n-3 and n-6 polyunsaturated fatty acids (PUFAs), which are crucial for neuronal tissue development. In this study, we evaluated the impact of feeding mice diets that are either deficient in α-linolenic acid (ALA) or supplemented with n-3 long-chain PUFAs from gestation to adolescence on the phospholipid and ganglioside composition of these tissues. Both diets modified the levels of some phospholipid classes, notably the phosphatidylserine and phosphatidylethanolamine levels. In addition, the low-ALA diet enriched n-6 PUFAs in the main phospholipid classes of both tissues, while the diet supplemented with n-3 PUFAs enhanced the n-3 PUFA-containing phospholipid species level, mainly in OM. The diets also modulated the levels and profiles of several ganglioside classes in OM and OB. These modifications may have repercussions on the olfactory sensitivity.

Keywords:  Ganglioside; Mass spectrometry; Olfactory bulb; Olfactory mucosa; Phospholipid; Polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.plefa.2023.102556
Transl Neurosci. 2023 Jan 01. 14(1): 20220277

Omega-3 polyunsaturated fatty acids alleviate early brain injury after traumatic brain injury by inhibiting neuroinflammation and necroptosis.

Yali Wu, Jing Zhang, Xiaoyan Feng, Wei Jiao.

  Presently, traumatic brain injury (TBI) is a leading contributor to disability and mortality that places a considerable financial burden on countries all over the world. Docosahexaenoic acid and eicosapentaenoic acid are two kinds of omega-3 polyunsaturated fatty acids (ω-3 PUFA), both of which have been shown to have beneficial biologically active anti-inflammatory and antioxidant effects. However, the neuroprotective effect of ω-3 PUFA in TBI has not been proven, and its probable mechanism remains obscure. We suppose that ω-3 PUFA can alleviate early brain injury (EBI) via regulating necroptosis and neuroinflammation after TBI. This research intended to examine the neuroprotective effect of ω-3 and its possible molecular pathways in a C57BL/6 mice model of EBI caused by TBI. Cognitive function was assessed by measuring the neuronal necroptosis, neuroinflammatory cytokine levels, brain water content, and neurological score. The findings demonstrate that administration of ω-3 remarkably elevated neurological scores, alleviated cerebral edema, and reduced inflammatory cytokine levels of NF-κB, interleukin-1β (IL-1β), IL-6, and TNF-α, illustrating that ω-3 PUFA attenuated neuroinflammation, necroptosis, and neuronal cell death following TBI. The PPARγ/NF-κB signaling pathway is partially responsible for the neuroprotective activity of ω-3. Collectively, our findings illustrate that ω-3 can alleviate EBI after TBI against neuroinflammation and necroptosis.

Keywords:  TBI; early brain injury; necroptosis; neuroinflammation; omega-3

DOI:  https://doi.org/10.1515/tnsci-2022-0277
J Cell Mol Med. 2023 Mar 06.

Importance of fatty acid binding proteins in cellular function and organismal metabolism.

Luis B Agellon.

  Fatty acid binding proteins (Fabps) are small soluble proteins that are abundant in the cytosol. These proteins are known to bind a myriad of small hydrophobic molecules and have been postulated to serve a variety of roles, yet their precise functions have remained an enigma over half a century of study. Here, we consider recent findings, along with the cumulative findings contributed by many laboratories working on Fabps over the last half century, to synthesize a new outlook for what functions Fabps serve in cells and organisms. Collectively, the findings illustrate that Fabps function as versatile multi-purpose devices serving as sensors, conveyors and modulators to enable cells to detect and handle a specific class of metabolites, and to adjust their metabolic capacity and efficiency.

Keywords:  Fabp; gene expression; metabolism; modulator; sensor; transporter

DOI:  https://doi.org/10.1111/jcmm.17703
Elife. 2023 Mar 07. pii: e68047. [Epub ahead of print]12

Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.

Bryn D Webb, Sara M Nowinski, Ashley Solmonson, Jaya Ganesh, Richard J Rodenburg, Joao Leandro, Anthony Evans, Hieu S Vu, Thomas P Naidich, Bruce D Gelb, Ralph J DeBerardinis, Jared Rutter, Sander M Houten.

  Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.

Keywords:  MCAT; genetics; genomics; human; mitochondria; mitochondrial disease

DOI:  https://doi.org/10.7554/eLife.68047
Int J Mol Sci. 2023 Mar 03. pii: 4908. [Epub ahead of print]24(5):

Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases.

Matthias Eckhardt.

  Sphingolipids containing acyl residues that are hydroxylated at C-2 are found in most, if not all, eukaryotes and certain bacteria. 2-hydroxylated sphingolipids are present in many organs and cell types, though they are especially abundant in myelin and skin. The enzyme fatty acid 2-hydroxylase (FA2H) is involved in the synthesis of many but not all 2-hydroxylated sphingolipids. Deficiency in FA2H causes a neurodegenerative disease known as hereditary spastic paraplegia 35 (HSP35/SPG35) or fatty acid hydroxylase-associated neurodegeneration (FAHN). FA2H likely also plays a role in other diseases. A low expression level of FA2H correlates with a poor prognosis in many cancers. This review presents an updated overview of the metabolism and function of 2-hydroxylated sphingolipids and the FA2H enzyme under physiological conditions and in diseases.

Keywords:  cancer; fatty acid 2-hydroxylase; fatty acid hydroxylase-associated neurodegeneration; hereditary spastic paraplegia; leukodystrophy; myelin; neurodegeneration; neurodegeneration with brain iron accumulation; skin; sphingolipids

DOI:  https://doi.org/10.3390/ijms24054908
Invest Ophthalmol Vis Sci. 2023 Mar 01. 64(3): 18

Tissue-Specific Sex Difference in Mouse Eye and Brain Metabolome Under Fed and Fasted States.

Meghashri Saravanan, Rong Xu, Olivia Roby, Yekai Wang, Siyan Zhu, Amy Lu, Jianhai Du.

Purpose: Visual physiology and various ocular diseases demonstrate sexual dimorphisms; however, how sex influences metabolism in different eye tissues remains undetermined. This study aims to address common and tissue-specific sex differences in metabolism in the retina, RPE, lens, and brain under fed and fasted conditions.
Methods: After ad libitum fed or being deprived of food for 18 hours, mouse eye tissues (retina, RPE/choroid, and lens), brain, and plasma were harvested for targeted metabolomics. The data were analyzed with both partial least squares-discriminant analysis and volcano plot analysis.
Results: Among 133 metabolites that cover major metabolic pathways, we found 9 to 45 metabolites that are sex different in different tissues under the fed state and 6 to 18 metabolites under the fasted state. Among these sex-different metabolites, 33 were changed in 2 or more tissues, and 64 were tissue specific. Pantothenic acid, hypotaurine, and 4-hydroxyproline were the top commonly changed metabolites. The lens and the retina had the most tissue-specific, sex-different metabolites enriched in the metabolism of amino acid, nucleotide, lipids, and tricarboxylic acid cycle. The lens and the brain had more similar sex-different metabolites than other ocular tissues. The female RPE and female brain were more sensitive to fasting with more decreased metabolites in amino acid metabolism, tricarboxylic acid cycles, and glycolysis. The plasma had the fewest sex-different metabolites, with very few overlapping changes with tissues.
Conclusions: Sex has a strong influence on eye and brain metabolism in tissue-specific and metabolic state-specific manners. Our findings may implicate the sexual dimorphisms in eye physiology and susceptibility to ocular diseases.

DOI: https://doi.org/10.1167/iovs.64.3.18
Autophagy. 2023 Mar 05. 1-3

Haste makes waste: staged suppression of autophagic-lysosomal pathway in microglia promotes the efficient clearance of myelin debris.

Chuan Qin, Yun-Hui Chu, Luo-Qi Zhou, Ming-Hao Dong, Wei Wang, Dai-Shi Tian.

  The autophagic-lysosomal pathway of microglia plays a key role in myelin debris removal in white matter damage. As the lipid-rich myelin debris are engulfed by microglia, the cellular autophagic level increases, accompanied by lysosomal dysfunction. However, several issues such as how to regulate this pathway to ensure the effective degradation of myelin debris, and maintain the balance of lipid metabolism are still to be elucidated. Recently, we have demonstrated that the excessive activation of macroautophagy/autophagy leads to lipid overload in lysosomes and lipid droplets accumulation, which could be the initiator of microglial dysfunction and secondary inflammatory white matter damage. Interestingly, staged suppression of autophagic activation in the acute phase of demyelination could benefit microglia allowing them to regain the lipid metabolism balance, and reduce the excessive accumulation of lipids, thus promoting the removal of myelin debris. The neuroprotective effects of microglial autophagy regulation may be related to intracellular linoleic acid (LA) production and PPARG pathway activation.

Keywords:  Autophagy; linoleic acid; microglia; myelin debris; staged suppression

DOI:  https://doi.org/10.1080/15548627.2023.2186097
J Inherit Metab Dis. 2023 Mar 07.

Competitive, multi-objective and compartmented Flux Balance Analysis for addressing tissue specific Inborn Errors of Metabolism.

Yanhua Liu, Hans V Westerhoff.

  The inborn error of metabolism Phenylketonuria (PKU, OMIM 261600) is most often due to inactivation of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) into tyrosine (Tyr). The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux Balance Analysis (FBA) of a single compartment model of PKU predicts that maximum growth rate should be reduced unless Tyr is supplemented. However, the PKU phenotype is lack of development of brain function specifically, and Phe reduction rather than Tyr supplementation cures the disease. Phe and Tyr cross the Blood Brain Barrier (BBB) through the aromatic amino acid transporter implying that the two transport reactions interact. However, FBA does not accommodate such competitive interactions. We here report on an extension to FBA that enables it to deal with such interactions. We built a three-compartment model, made the common transport across the BBB explicit, and included dopamine and serotonin synthesis as parts of the brain function to be delivered by FBA. With these ramifications, FBA of the Genome scale Metabolic Model extended to three compartments does explain that (i) the disease is brain specific, (ii) phenylpyruvate in urine is a biomarker, (iii) excess of blood-phenylalanine rather than shortage of blood-tyrosine causes brain pathology, and (iv) Phe deprivation is the better therapy. The new approach also suggests (v) explanations for differences in pathology between individuals with the same PAH inactivation, and (vi) interference of disease and therapy with the functioning of other neurotransmitters. This article is protected by copyright. All rights reserved.

Keywords:  Competitive Flux Balance Analysis; Inborn Errors of Metabolism; Multiple-Compartment Model; Phenylketonuria; Systems Biology

DOI:  https://doi.org/10.1002/jimd.12603
Front Neurosci. 2023 ;17 1137893

Sphingolipids in neurodegenerative diseases.

Xueyang Pan, Debdeep Dutta, Shenzhao Lu, Hugo J Bellen.

  Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich's ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.

Keywords:  Drosophila; Parkinson’s disease; ceramides; lysosome; mitochondria; neurodegeneration; sphingolipids

DOI:  https://doi.org/10.3389/fnins.2023.1137893
Int J Mol Sci. 2023 Feb 23. pii: 4403. [Epub ahead of print]24(5):

Lipids at the Nexus between Cerebrovascular Disease and Vascular Dementia: The Impact of HDL-Cholesterol and Ceramides.

Domenico Sergi, Enrico Zauli, Veronica Tisato, Paola Secchiero, Giorgio Zauli, Carlo Cervellati.

  Cerebrovascular diseases and the subsequent brain hypoperfusion are at the basis of vascular dementia. Dyslipidemia, marked by an increase in circulating levels of triglycerides and LDL-cholesterol and a parallel decrease in HDL-cholesterol, in turn, is pivotal in promoting atherosclerosis which represents a common feature of cardiovascular and cerebrovascular diseases. In this regard, HDL-cholesterol has traditionally been considered as being protective from a cardiovascular and a cerebrovascular prospective. However, emerging evidence suggests that their quality and functionality play a more prominent role than their circulating levels in shaping cardiovascular health and possibly cognitive function. Furthermore, the quality of lipids embedded in circulating lipoproteins represents another key discriminant in modulating cardiovascular disease, with ceramides being proposed as a novel risk factor for atherosclerosis. This review highlights the role of HDL lipoprotein and ceramides in cerebrovascular diseases and the repercussion on vascular dementia. Additionally, the manuscript provides an up-to-date picture of the impact of saturated and omega-3 fatty acids on HDL circulating levels, functionality and ceramide metabolism.

Keywords:  HDL-cholesterol; ceramides; cerebrovascular disease; omega-3 fatty acids; saturated fatty acids; vascular dementia

DOI:  https://doi.org/10.3390/ijms24054403
Neuromuscul Disord. 2023 Feb 19. pii: S0960-8966(23)00027-5. [Epub ahead of print]33(4): 315-318

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Ayca Burcu Kahraman, Yılmaz Yildiz, Hulya Gokmen-Ozel, Sibel Kadayifcilar, Serap Sivri.

  Early-onset long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a fatty acid β-oxidation disorder with a poor prognosis. Triheptanoin, an anaplerotic oil with odd-chain fatty acids can improve the disease course. The female patient presented here was diagnosed at the age of 4 months, and treatment was started as fat restriction, frequent feeding, and standard medium-chain triglyceride supplementation. In follow-up, she had frequent rhabdomyolysis episodes (∼8 per year). At the age of six, she had 13 episodes in 6 months, and triheptanoin was started as part of a compassionate use program. Following unrelated hospital stays due to multisystem inflammatory syndrome in children and a bloodstream infection, she had only 3 rhabdomyolysis episodes, and hospitalized days decreased from 73 to 11 during her first year with triheptanoin. Triheptanoin drastically decreased the frequency and severity of rhabdomyolysis, but progression of retinopathy was not altered.

Keywords:  Fatty acid oxidation disorders; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Multisystem inflammatory syndrome in children (MISC); Retinopathy; Rhabdomyolysis; Triheptanoin

DOI:  https://doi.org/10.1016/j.nmd.2023.02.008
Curr Med Chem. 2023 Mar 08.

The effect of statins on the differentiation and function of central nervous system cells.

Sajjad Chamani, Leila Mobasheri, Shadi Zerehpoosh, Ali Naghizadeh, Alice P McCloskey, Manfredi Rizzo, Tannaz Jamialahmadi, Amirhossein Sahebkar.

  Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation, and oxidative stress. The effect of statins on the central nervous system (CNS), particularly on cognition and neurological disorders such as cerebral ischemic stroke, multiple sclerosis (MS), and Alzheimer's disease (AD), has received increasing attention in recent years, both within the scientific community and in the media. This review aims to provide an updated discussion on the effects of statins on the differentiation and function of various nervous system cells, including neurons and glial cells. Additionally, the mechanisms of action and how different types of statins enter the CNS will be discussed.

Keywords:  Central nervous system; Neurodegeneration; Pleiotropic effect; Statins; inflammation; plasma cholesterol

DOI:  https://doi.org/10.2174/0929867330666230308121645